Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults and has a global incidence of 1-2.6/100,000 annually. Known risk factors include age, certain genetic mutations, and male sex prior to older age. With largely unknown etiology, identifying modifiable risk factors for ALS is an important approach to minimizing the burden of this disease; however, findings have been inconsistent for environmental risk factors for ALS, such as metal, solvent, and pesticide exposure and past studies have been limited in their ability to examine the presence of genetic mutations with individual level risk factors for ALS and gene- environment interactions. Although ambient air pollutants have been examined with regard to other neurologic conditions, such as Parkinson?s disease and Alzheimer?s disease, only one study to date has explored the potential relationship with ALS. The study aims to investigate associations of environmental and occupational exposures including persistent environmental toxicants and ambient air pollutants and ALS. A case control study is proposed and will involve identification of persons with ALS from the National ALS Registry with available biorepository samples and risk factor data (cases, n=330), and recruitment of controls from the same county or state matched by age, race, and sex (n=330). The questionnaire will obtain information on sociodemographic factors, smoking history, military service history, environmental/occupational exposures (pesticides, metals, solvents), and lifetime residential and occupational history, as available. Environmental/occupational exposures (i.e., self-report and ambient air pollutants) will be examined in relation to ALS risk with verification of toxicant levels in blood samples. Residential history will be used to calculate a time weighted average exposure of PM2.5 and ozone for the period 2002-2012. Data on 35 neurotoxic air pollutants identified through the US EPA National-Scale Air Toxics Assessment (NATA) will be used to calculate average annual average residential exposure for cases and controls for available NATA years (1999, 2002, 2005, and 2011). We will measure exposures to solvents and pesticides in blood concentrations of cases (n=330) and controls (n=330) using a battery of tests for persistent environmental pollutants (organochlorine pesticides, polychlorinated biphenyls, and brominated flame retardants). This will help verify the responses for estimated exposures. Odds ratios and 95% CIs will be estimated using conditional logistic regression with adjustment for demographics, confounders, and smoking. Additionally, among ALS cases (n=330), we will examine the functional relationship between environmental toxicants in human biological samples and key biological pathways and common genes (e.g., C9ORF72, SOD1, NEK1) associated with the development and/or progression of ALS. The proposed study will be one of the first to examine blood levels of environmental toxicants and presence of genetic mutations in combination with data on environmental and occupational exposures from interview data (i.e., self-report and ambient air pollutants) in relation to ALS risk.